Resting state effective connectivity abnormalities of the Papez circuit and cognitive performance in multiple sclerosis

The Papez circuit is central to memory and emotional processes. However, little is known about its involvement in multiple sclerosis (MS). We aimed to investigate abnormalities of resting state (RS) effective connectivity (EC) between regions of the Papez circuit in MS and their relationship with cognitive performances. Sixty-two MS patients and 64 healthy controls (HC) underwent neuropsychological assessment, 3D T1-weighted, and RS functional MRI. RS EC analysis was performed using SPM12 and dynamic causal modeling. RS EC abnormalities were investigated using parametric empirical Bayes models and were correlated with cognitive scores. Compared to HC, MS patients showed (posterior probability > 0.95) higher EC between the right entorhinal cortex and right subiculum, and lower EC from the anterior cingulate cortex (ACC) to the posterior cingulate cortex (PCC), from left to right subiculum, from left anterior thalamus to ACC, and within ACC and PCC. Lower RS EC from the ACC to the PCC correlated with worse global cognitive scores (rho = 0.19; p = 0.03), worse visuospatial memory (rho = 0.19; p = 0.03) and worse semantic fluency (rho = 0.21; p = 0.02). Lower RS EC from the left to the right subiculum correlated with worse verbal memory (rho = 0.20; p = 0.02), lower RS EC within the ACC correlated with worse attention (rho = -0.19; p = 0.04) and more severe brain atrophy (rho = -0.26; p = 0.003). Higher EC from the right entorhinal cortex to right subiculum correlated with worse semantic fluency (rho = 0.21; p = 0.02). In conclusion, MS patients showed altered RS EC within the Papez circuit. Abnormal RS EC involving cingulate cortices and hippocampal formation contributed to explain cognitive deficits.